Despite advancements in prenatal care, preterm birth continues to rise in the United States, with rates now exceeding 12.7%. Although treatments, such as cerclage and administration of exogenous progesterone have demonstrated benefit in women with a prior history of preterm birth or a short cervix by transvaginal sonography, the impact of these interventions is limited by the lack of sensitivity of these markers to identify the majority of women at risk for preterm birth. Complicating the issue is that preterm birth has increasingly been recognized to be the outcome of four separate biologic pathways (uterine distention, inflammation, decidual hemorrhage, and premature activation of the Maternal-Fetal Hypothalamic-Pituitary Adrenal (HPA) axis) all of which may not be amenable to these treatment strategies. Biologic evidence would suggest that preterm birth secondary to premature activation of the HPA axis would be amenable to treatment with exogenous progesterone;and may be the means by which racial disparities and maternal stress contribute to preterm birth. Recently, two reports have suggested that ultrasonography of the fetal adrenal gland during the early third trimester is a highly sensitive and specific short term predictor of spontaneous preterm birth. This would suggest that measurement of the fetal adrenal gland correlates with activation of the HPA axis. Nonetheless, these studies are limited by small numbers of patients, lack of a broadly validated technique, short duration of prediction, and failure to correlate with other markers of activation of the HPA axis. Our proposed study will evaluate the performance of ultrasound measurement of the fetal adrenal gland between 24 0/7 weeks to 28 0/7 weeks to predict spontaneous preterm birth in a cohort of 2,000 nulliparous women as part of a larger NICHD prospective observational trial of nulliparous women (NuMOM2b study). The primary outcome of our investigation will be spontaneous preterm birth, defined as spontaneous birth prior to 37 0/7 weeks. Moreover, we will fully assess the test characteristics of ultrasound of the fetal adrenal gland as to inter and intra-observer reliability. Through the efforts of the NuMOM2b study, we will further define the maternal-fetal HPA axis pathway by comparing measurements of the fetal adrenal gland with its antecedent causes (maternal stress, fetal growth restriction, etc), maternal biological responses (estradiol, progesterone, etc.) and fetal-placental mediators (CRH, fetal DHEA-S, etc). If successful, this study will be the first to define a fetally based marker of preterm birth and fully define this important pathway of preterm birth. PUBLIC HEALTH RELEVANCE: Our investigation will assess the ability of a novel ultrasound marker (size of the fetal adrenal gland) to predict spontaneous preterm birth amongst women having their first child. This information coupled with biochemical markers of premature activation of the maternal-fetal hypothalamic pituitary adrenal axis will come to fully define this important pathway as a cause of preterm birth. This line of research could lead to improved detection of women at risk preterm birth and lead to an intervention trial using exogenous progesterone.